Hereditary insensitivity to pain with anhidrosis: genes and variants

Genes linked to Hereditary insensitivity to pain with anhidrosis

• NTRK1: High affinity nerve growth factor receptor

  Nerve-growth-factor signaling through this pathway supports survival and differentiation of sensory and sympathetic neurons. Loss-of-function variants cause congenital insensitivity to pain with anhidrosis, whereas oncogenic NTRK1 fusions can drive diverse cancers.

  34 disease-causing and 362 uncertain variants in NTRK1 are linked to Hereditary insensitivity to pain with anhidrosis.

Where Hereditary insensitivity to pain with anhidrosis variants cluster

• NTRK1 Protein kinase (positions 510–781): 27 of 34 disease-causing changes, 2.3× more than its size predicts.

Known disease-causing variants in Hereditary insensitivity to pain with anhidrosis

Uncertain variants in Hereditary insensitivity to pain with anhidrosis that look disease-causing

Which prediction tools work for Hereditary insensitivity to pain with anhidrosis

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 87 out of 100
• SIFT: 84 out of 100
• phyloP: 64 out of 100

Diseases related to Hereditary insensitivity to pain with anhidrosis

• Charcot-Marie-Tooth disease, also linked to NTRK1
• Ovarian cancer, also linked to NTRK1
• Colorectal cancer, also linked to NTRK1
• Non-small cell lung carcinoma, also linked to NTRK1
• Familial medullary thyroid carcinoma, also linked to NTRK1

Frequently asked questions

Which genes are linked to Hereditary insensitivity to pain with anhidrosis?

In CATVariant, Hereditary insensitivity to pain with anhidrosis is linked to 1 analyzed protein: NTRK1 (High affinity nerve growth factor receptor).

How many genetic variants are linked to Hereditary insensitivity to pain with anhidrosis?

415 variants: 34 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 362 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hereditary insensitivity to pain with anhidrosis look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example NTRK1 R692C, NTRK1 V715M and NTRK1 V715A. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Hereditary insensitivity to pain with anhidrosis?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.87, based on 23 disease-causing and 21 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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